Pain plays a physiologically important role as a warning reaction to know danger. On the other hand, pain is also a significant cause to lower quality of lives (QOL) of patients. Pain accompanying almost all diseases typified by rheumatic diseases is one of causes of dysfunction. Accordingly, it is medically very important to control pain (Experimental Medicine, 18 (17), 2332-2337 (2000) and J. Pharm. Soc., 120 (12), 1291-1307 (2000)).
Narcotic analgesics such as morphine and nonnarcotic analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs), indometacin and diclofenac sodium, are widely used now as drugs which control pain.
However, while the narcotic analgesics have strong analgesic actions, they have side effects such as drug dependence, and their use are strictly limited accordingly. On the other hand, NSAIDs are very useful as therapeutic agents for pain derived from synthesis of inflammatory mediators such as prostaglandin but have no strong analgesic actions unlike the narcotic analgesics.
In recent years, μ (mu), κ (kappa) and δ (delta) receptors have been proposed as subtypes of the opioid receptors, and it has been clarified that the side effects such as drug dependence of morphine are exhibited through the κ opioid receptor. Further, it has been found that analgesic actions are exhibited through any of the μ opioid receptor, the κ opioid receptor and the δ opioid receptor.
These findings suggest a possibility that drugs which selectively act on the κ opioid receptor and the δ opioid receptor can be analgesics which solve problems of drugs which act on the μ opioid receptor.
Compounds reported to serve as drugs which selectively act on the κ opioid receptor are compounds having a phenylacetic amide skeleton represented by U50488H, compounds having a benzodiazepine skeleton represented by Thifuadom, compounds having a phenothiazine skeleton represented by Apadoline, compounds having a 4,5-epoxymorphinan skeleton represented by TRK-820 and the like (“All of opioid”, published by Mikusu Co., Ltd., p. 222-229 (1999)).
It is known that pain is weaken by activating the κ opioid receptor, and it was reported that a κ opioid receptor agonist is useful as an analgesic (“All of opioid”, published by Mikusu Co., Ltd., p. 25-36 (1999)). Further, it was also reported that the κ opioid receptor agonist has an antipruritic action (WO 98/23290).
On the other hand, Japanese Laid-open Patent Publication Nos. 46079/1983, 67276/1984, 139679/1985 and 221679/1987 reported that 2-phenylbenzothiazoline derivatives have calcium antagonism and platelet aggregation actions and are useful as therapeutic agents for cardiovascular diseases such as hypertension, thrombosis, angina and arrhythmia.
However, actions of these 2-phenylbenzothiazoline derivatives on the κ opioid receptor are not known, much less it is impossible to presume which derivatives thereof act as agonists or antagonists at all. Their analgesic actions and antipruritic actions are not reported at all, either.
It is very interesting subjects to find new pharmacological actions of the known 2-phenylbenzothiazoline derivatives, which are useful as pharmaceuticals, and further to synthesize novel 2-phenylbenzothiazoline derivatives, which are their analogs, and to find useful pharmacological actions thereof.